Our goal is to develop effective radioimmunotherapy using humanized monoclonal antibodies for metastatic and/or recurrent breast cancer. We propose to evaluate and overcome two obstacles: the limited ability to deliver tumoricidal radiation doses by this method alone and the immunogenicity of the immunoconjugates. We have utilized a new, humanized BrE-3 monoclonal antibody directed against a 400-kD breast epithelial mucin antigen and labeled it with a 111Indium (111In) MX- DTPA metal chelator. We detected 86% of 72 known lesions in 12/15 patients. All the patientsU tumors expressed the BrE-3 antigen, as assessed by immunohistochemical staining of previously obtained tissue. Biological half-life of radiolabeled antibody in serum measured by HPLC averaged 56125.4 hours across all patients. Toxicity was mild and predictable; however, human anti-mouse IgG antibody was detected after treatment in 7/15 patients. We hypothesize that humanized BrE-3 monoclonal antibody complexed with 90Yttrium (90Y) will be an effective therapy against metastatic breast carcinoma and that combining this therapy with topotecan will enhance efficacy. Continuous infusion of a topoisomerase I inhibitor, explored extensively at NYU, has shown activity in breast cancer in phase-I trials with minimal toxicity. In the mouse model, the novel combination of these two agents provides significant therapeutic efficacy over each agent alone. Our specific aims are as follows: 1) to develop effective radioimmunotherapy of breast cancer using a fractionated dose regimen and 90Y MX-DTPA humanized anti-BrE-3; 2) to determine the maximum tolerated dose (MTD) using combined dose-fractionated 90Y MX-DTPA humanized BrE-3 antibody and continuous infusion topotecan in a phase-I dose-escalation trial; and 3) to assess the potential efficacy of combined 90Y MX-DTPA humanized BrE-3 and topotecan at MTD in a phase-II clinical trial in patients with metastatic or recurrent breast cancer.